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MITOTIC REGULATION IN OVARIAN EPITHELIAL TUMORS APPROACHING
IN VITRO CRISIS
by
Vanessa Yu
________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
August 2009
Copyright 2009 Vanessa Yu

Crisis, a mortality checkpoint, is characterized by widespread apoptosis. We previously showed that epithelial cell strains derived from benign ovarian cystadenomas and further transfected with SV40 Large T Antigen undergo polyploidy followed by aneuploidy as they approach in vitro crisis. I sought to investigate the mechanisms behind these changes, which may recapitulate those that take place during tumor development, especially for those tumors that have a near polyploid number of chromosomes. I first tested the hypothesis that the initial doubling in DNA content, which appears to trigger the entire process, reflects a cell cycle arrest. I revealed that a mitotic arrest, which is maintained at the spindle checkpoint between metaphase to anaphase transition, is the main determinant of ploidy dependent crisis. Further investigation into the mechanism behind regulation of this arrest showed that down-regulation of BRCA1 expression, a protein controlling familial ovarian cancer predisposition, allowed cells to overcome such mitotic arrest and re-enter the cell cycle without completion of cytokinesis, leading to tetraploidy and aneuploidy. Aurora A, a known upstream regulator of BRCA1, was found to be over-expressed in cells approaching crisis. Further studies revealed a novel role for Aurora A in controlling BRCA1 expression during ploidy dependent crisis. I conclude that over-expression of Aurora A inhibits BRCA1 expression during ploidy dependent crisis, leading to escape from mitotic arrest and acquisition of tetraploidy, and subsequent aneuploidy development.

MITOTIC REGULATION IN OVARIAN EPITHELIAL TUMORS APPROACHING
IN VITRO CRISIS
by
Vanessa Yu
________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
August 2009
Copyright 2009 Vanessa Yu